BIOCHEMISTRY OF RENIN SECRETION

肾素分泌的生物化学

• 批准号: 2138338
• 负责人: Willa A Hsueh
• 金额: $ 25.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-07-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2138338
• 关键词: X ray crystallography; angiotensin /renin /aldosterone hypertension; antihypertensive agents; biochemistry; captopril; diabetes mellitus; diabetic nephropathy; electron microscopy; human genetic material tag; human subject; kidney circulation; lipoxygenase; nifedipine; prostacyclins; prostaglandins; renal hypertension; renin; transfection

A defect in prorenin processing which may be intimately related to the nephropathy and hypertension of diabetes mellitus will be the focus of this collaborative investigation. The objective of this investigation is to define specific molecular and cellular defects in prorenin processing in diabetes and to determine whether this defect can be normalized by antihypertensive treatment which may retard the progression of nephropathy. This will be accomplished by the following goals: (1) Determine the structure of human recombinant prorenin by x-ray crystallographic analysis. This will allow us to identify specific sites in the prorenin molecule involved in (a) activation of renin, (b) interaction with the processing enzyme, or (c) regulation of intracellular sorting. (2) Use cultured AtT- 20 cells transfected with the human renin gene as a model system of constitutive and regulated secretion of prorenin and renin, respectively. We will determine how specific blocks in the regulated pathway affect constitutive secretion. (3) Evaluate structural or biochemical lesions in the diabetic kidney which could lead to increased prorenin production. Electron microscopy (EM) immunohistochemistry and measurement of prorenin processing activity will be performed on renal biopsy specimens from patients with and without diabetes mellitus and compared to results in AtT- 20 cells. (4) Determine the effect of antihypertensive treatment on diabetic nephropathy and plasma prorenin levels. We will assess the relationships between prorenin, albumin excretion, renal hemodynamics, and postaglandins and lipoxygenase products before and after therapy with inhibitors of the renin system. The knowledge of prorenin structure (Aim 1) will support identification of prorenin processing defects in an in vitro system (Aim 2) and in vivo (Aim 3). Application of these data to diabetics with nephropathy and hypertension may lead to a rational new approach to treatment (Aim 4).

prorenin处理的缺陷，可能与 肾病和糖尿病的高血压将成为其中的重点 协作调查。 这项调查的目的是 定义特异性分子和细胞缺陷在prorenin加工中 糖尿病并确定是否可以通过 降压治疗可能会阻碍肾病的进展。 这将通过以下目标来实现：（1）确定 通过X射线晶体学分析，人重组培养剂的结构。 这将使我们能够识别prorenin分子中的特定位点 参与（a）激活肾素，（b）与处理的相互作用 酶，或（c）调节细胞内分选。 （2）使用培养的att- 20个细胞用人肾素基因作为模型系统转染 prorenin和renin的组成型和调节分泌。 我们将确定受监管途径中的特定块如何影响 构成分泌。 （3）评估结构或生化病变 糖尿病性肾脏可能导致prorenin产生增加。 电子显微镜（EM）免疫组织化学和prorenin的测量 处理活动将对肾脏活检标本进行 患有和患有糖尿病的患者，并将 20个细胞。 （4）确定降压治疗对 糖尿病性肾病和血浆prorenin水平。 我们将评估 prorenin，白蛋白排泄，肾脏血液动力学和 postaglandins和lipoxygoxyase产品在治疗前后 肾素系统的抑制剂。 prorenin结构的知识（目标 1）将支持识别An中的prorenin处理缺陷 体外系统（AIM 2）和体内（AIM 3）。 将这些数据应用于 患有肾病和高血压的糖尿病患者可能会导致新的新 治疗方法（目标4）。